The invention relates to antiviral agents, and more specifically to antiviral therapy.
One of the great paradoxes of modem medicine is that the simplest of organisms can be the most difficult to control. While great progress has been made in controlling more complex organisms such as bacteria, with hundreds of different antibacterial pharmaceutical compositions or antibiotics, there are very few pharmaceutical compositions intended or adapted for antiviral therapy that are of proven effectiveness.
The major drawback in developing antiviral agents has been an inability to distinguish viral replicative mechanisms from host replicative processes. Nevertheless, progress has been made over the past two decades in discovering molecules necessary for virus replication, in characterising them mechanistically, and in developing antiviral agents to inhibit them (see, for review, Hirsch et al., In: Fields Virology, Chapter 15, (Lippincot-Raven Publishers, 1996). Well known antiviral agents include amantadine, rimandatine and other anti-influenza agents, acyclovir, gangcyclovir and related agents, foscarnet and other anti-herpes virus agents, ribavirine and various antiretroviral agents as discussed below.
Progress and understanding in the field of antiretroviral therapy in the past few years has been dramatic (see, Hammer and Yeni. AIDS, 12:S181-S188, (1998)). Three major advances have fuelled progress. First, increasing knowledge of disease pathogenesis has provided underpinnings for current therapeutic rationale. The proliferative nature of the viral replicative process (1010 virions produced and destroyed each day), the rapid viral turnover (virion plasma half-life of 6 h or less), and the recognition of second and third phases of viral decay under the influence of potent antiretroviral therapy resulting from the presence of longer-lived cell reservoirs has guided the current principles of antiretroviral therapy. The second advance has been the widening array of therapeutic choices represented by the increasing numbers of agents available to patients and clinicians. Third, the availability of increasingly sophisticated patient monitoring techniques, such as viral load determinations, has simultaneously provided the tools for dissecting HIV disease pathogenesis and monitoring the effects of treatment in affected individuals. Taken together, these developments have led to the generally accepted principle that potent combination regimens (also called xe2x80x9chighly active antiviral therapyxe2x80x9d or xe2x80x9cHAARTxe2x80x9d) designed to drive and maintain plasma HIV-RNA concentration below the limits of detection of currently available assays are the treatments of choice.
However, a number of practical limitations to this idealised approach have increasingly been recognised. These include: the variability of initial virologic response according to the disease stage, particularly the high rate of failure in those with advanced HIV infection; the challenge of patient adherence to complex regimens; drug failure and the threat of multidrug resistance; the lack of predictably effective salvage therapies; the emergence of longer-term toxicities to the protease inhibitor class of compounds; and the sharpening division between populations of the world related to cost and access to effective agents.
In several countries, there are 11 agents approved for the treatment of HIV infection and the reasonable expectation is that the total will rise to 15 shortly. These agents are either HIV reverse transcriptase inhibitors of the nucleoside, non-nucleoside, and nucleotide subclasses or members of the HIV-protease inhibitor class. Although the simple calculation of the number of two-, three- and four-drug combinations would suggest that the regimen choices for initial and alternative therapies are vast, in reality they are much more limited as a result of cross-resistance, toxicities, tolerance, drug or food interactions and other practical considerations. Thus, although it is true that the options for initial potent, combination regimens are increasing, when one considers the limitations on subsequent regimens conferred by the initial choice, one realises the restricted options for long-term virologic suppression that currently exist.
In areas where drug access is not a problem, the current recommended standard for initial therapy is a potent in vivo protease inhibitor combined with two nucleoside analogs with the first alternative being a non-nucleoside reverse transcriptase inhibitor in combination with two nucleoside analogs. However, the emergence of drug resistance during treatment and its association with treatment failure have been described with nearly all of the antiretroviral agents in use or in development. Therefore, resistance testing might be thought to logically assist with the choice of alternative treatment in the setting of treatment failure and assist with the choice of initial therapy when primary drug resistance is suspected. However, many questions exist that need to be answered before resistance testing (either genotypic or phenotypic) becomes accepted as a routine clinical tool. In what setting and to what extent this technology will improve decision-making is not clear and drug resistance is only one of a number of reasons for treatment failure. Resistance testing results are most reflective of the selective pressure of the current drug that might emerge quickly on a new regimen. Further, one cannot always deduce the phenotypic susceptibility of a viral strain from its genotype because of assay sensitivity and resistance mutational interactions. Cross-resistance, particularly to protease inhibitors, may also be a dynamic process in which viruses are xe2x80x9cprimedxe2x80x9d by mutations selected on a previous therapy to develop resistance more quickly when exposed to a new member of the same drug class.
Failure of a particular antiretroviral drug regimen may be defined clinically, immunologically or virologically. Increasingly, for individuals on their initial drug combination, a strict definition of failure is being applied, that is, detectable viremia following previous suppression below the detection below the detection limit of the assay being employed. With the advent of plasma HIV-RNA assays with detection limits at the approximate 50 copies/ml range, this has raised the question of whether a confirmed rise above this threshold should trigger a treatment change given the still limited therapeutic armamentarium.
The advances and the limitations of the currently available antiretroviral agents make it clear that new agents and combinations are urgently needed. On the immediate horizon is the promise of widespread availability of four new agents: abacavir (a nucleoside analog reverse transcriptase inhibitor), efavirenz (a non-nucleoside reverse transcriptase inhibitor), adefovir dipivoxil (a nucleotide reverse transcriptase inhibitor), and amprenavir (a protease inhibitor). These agents will carry with them an increasing number of choices for patients and clinicians but are most likely to benefit antiretroviral-naive or minimally drug-experienced individuals only. Their role in xe2x80x9csalvagexe2x80x9d regimens is currently under investigation but the potential for cross-resistance with the currently approved agents may well limit their effectiveness in this circumstance.
In conclusion, a next wave of drug development is needed that involves new classes of antiviral agents. Other potential anti-viral agents effective against viral targets are needed to broaden the therapeutic possibilities of viral therapy.
The invention provides a method for treating a viral infection with a first antiviral agent, said infection caused by a virus that is at least partly resistant to a second antiviral agent, in a subject suffering therefrom, said method comprising administering to said subject said first antiviral agent, it being a compound of the general formula 
wherein X and Y are independently O, S, SO, SO2, SO3, but preferably O, S, SO2.
xe2x80x9cnxe2x80x9d is an integer between 0 and 4 inclusive, preferably 1 or 2.
R and Rxe2x80x2 are independently H with the proviso that when R is H, Rxe2x80x2 is not H, a C1-C10, branched or unbranched, substituted or unsubstituted (preferably the substitute is one or more of halogen or CF3), saturated or (poly)unsaturated, (cyclo)alkyl, alkene, alkyn, (cyclo)aryl, aryl(cyclo)alkyl, (cyclo)alkylaryl, alkoxyaryl, alkoxyalkene, alkoxyalkyne, enyne, diene, diyne or alkoxyalkyl, preferably selected from the group consisting of H, CH3, CF3, CH2Cl, CH2Br, CH2CH3, (CH2)2CH3, (CH2)3CH3, (CH2)4CH3, (CH2)5CH3, (CH2)6CH3, CH(CH3)2, CH(CH3)3, CHxe2x95x90Cxe2x95x90CH2, (CH2)2O(CH2)3CH3, CH2HCxe2x95x90CH(CH2)3CH3, CH2Cxe2x89xa1C(CH2)3CH3, CH2Cxe2x89xa1C(CH2)2CH3 CH2Cxe2x89xa1CCH2CH3, CH2Cxe2x89xa1CCH3 and CH2Cxe2x89xa1CH and isomers or homologues thereof; and wherein Rxe2x80x2 is R, preferably selected from the group consisting of H, CH3,; and wherein R or Rxe2x80x2 may contain ether linkages or carbonyl or thiocarbonyl functions attached to the ring structure such as ringxe2x80x94(Cxe2x95x90O/S)xe2x80x94R/Rxe2x80x2 and Z is independently R, Rxe2x80x2, XR, XRxe2x80x2, YR or YRxe2x80x2 or a functional equivalent, such as a pharmaceutically acceptable salt or hydrate, thereof.
The invention also provides a method for treating a viral infection with a first antiviral agent, said infection caused by a virus that is at least partly resistant to a second antiviral agent, in a subject suffering therefrom, said method comprising administering to said subject said first antiviral agent, it being a compound of the general formula 
or a functional equivalent, such as a pharmaceutically acceptable salt or hydrate, thereof, in particular wherein R is selected from the group consisting of H, CH3, CH2CH3, (CH2)2CH3, (CH2)3CH3, (CH2)4CH3, (CH2)5CH3, (CH2)6CH3, CH(CH3)2, CH(CH3)3, CHxe2x95x90CHxe2x95x90CH2, (CH2)2O(CH2)3CH3, CH2HCxe2x95x90CH(CH2)3CH3, CH2Cxe2x89xa1C(CH2)3CH3, CH2Cxe2x89xa1C(CH2)2CH3, CH2Cxe2x89xa1CCH2CH3, CH2Cxe2x89xa1CCH3 and CH2Cxe2x89xa1CH and isomers or homologues thereof and Rxe2x80x2 is selected from the group consisting of H, CH3, CF3, CH2CL and CH2Br.